Recent genetic and genomic studies have identified a large number of candidate genes for autism spectrum disorders (ASDs), many of which encode synaptic proteins, suggesting synaptic dysfunction may play a critical role in ASDs. One of the most promising ASD candidate genes is Shank3. Shank family proteins (Shank1-3) directly bind SAPAP to form the PSD95/SAPAP/Shank complex. This core of proteins is thought to function as a scaffold, orchestrating the assembly of the macromolecular postsynaptic signaling complex. They have been proposed to play important roles in trafficking and anchoring of postsynaptic ionotropic glutamate receptors and the development of glutamatergic synapses. Shank3 is the only member of the Shank family highly expressed in the striatum, a brain region strongly implicated in ASDs. To investigate the in vivo function of Shank3 at synapses and to elucidate how a disruption of Shank3 may lead to ASDs, we generated Shank3 mutant mice. We found that disruption of Shank3 resulted in both structural and functional changes in cortico-striatal synapses. Furthermore, Shank3 mutant mice exhibit compulsive/repetitive behavior and impaired social interaction, which resemble two of the cardinal features of ASDs. Together, our studies demonstrate a critical role for Shank3 in cortico-striatal synaptic structure and function n vivo and establish causality between a disruption in the Shank3 gene and the genesis of autistic like-behaviors in mice. Thus, the Shank3 mutant mice provide us with an excellent opportunity to dissect the neural circuitry mechanisms underlying the abnormal behaviors relevant to human ASD. We propose to combine genetic, optogenetic, electrophysiological and behavioral approaches to achieve the following goals: (1) To investigate the intrastriatal microcircuitry dysfunction in Shank3 mutant mice. (2) To determine the relative contributions of the direct and indirect pathway of the basal ganglia in repetitive behavior. (3) To dissect neural circuits involved in social interaction deficits in Shank3 mutant mice. Together, these studies may significantly enhance our understanding of neural circuitry mechanisms of autistic-like behaviors and may help to develop novel strategies for more effective treatment. PUBLIC HEALTH RELEVANCE: Autism spectrum disorders (ASDs) are a group of common and devastating neurodevelopmental disorders. Currently, there is no effective treatment for ASDs. The goal of this research is to use mutant mice as a model system to elucidate the pathological mechanisms of ASDs. These studies could lead to better understanding of neural mechanisms underlying ASD-like behaviors and the identification of potential targets for the development of effective treatments.